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Preparation and Diels-Alder reaction of a reactive, electron-deficient heterocyclic azadiene: dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate. 1,2-diazine (dimethyl 4-phenyl-1,2-diazine-3,6-dicarboxylate) and pyrrole (dimethyl 3-phenylpyrrole-2,5-dicarboxylate) introduction intermediate: Disodium dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate intermediate: Dihydro-1,2,4,5-tetrazine-3,6-dicarboxylic acid intermediate: Dimethyl dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate product: Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate product: Dimethyl 4-phenyl-1,2-diazine-3,6-dicarboxylate product: Dimethyl 3-phenylpyrrole-2,5-dicarboxylate byproduct: methyl 3-phenyl-5-carboxamidopyrrole-2-carboxylate Keywords: annulation, heterocyclic-[5]; annulation, heterocyclic-[6]; annulation, heterocyclic-[6]; cyclization, cycloaddition; Diels-Alder reactions; esterification, of dicarboxylic acids; oxidation, miscellaneous; reduction, miscellaneous; ring contraction reactions; methanol; nitrous gases, generation; zinc dust, activation; diazo compounds; dioxane, cancer suspect agent; nitrous gases, toxic; nitrous gases, toxic

Diabetes mellitus has been declared to be at an epidemic level by the World Health Organization. The syndrome is characterised as either Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus. Impaired glucose tolerance for extended periods of time results in serious complications such as kidney damage and impaired blood circulation and is the main cause for blindness and amputations in patients with diabetes. A combination of life-style change, dietary change and oral medications can treat Type II diabetes mellitus effectively and prevent long-term complications. Combination therapy appears to be the most effective approach in controlling blood glucose levels. This review updates the progress made in medicinal chemistry towards promising biological targets, with the development of a new generation of small molecules having improved efficacy and safety profiles.

The occurrence of hypoxia-ischemia (HI) during early fetal or neonatal stages of an individual leads to the damaging of immature neurons resulting in behavioral and psychological dysfunctions, such as motor or learning disabilities, cerebral palsy, epilepsy or even death. No effective treatment is currently available and this study is the first to use hyperbaric oxygen (HBO) as a treatment for neonatal HI. Herein, we sought out to determine if HBO is able to offer neuroprotectivity against an HI insult. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O(2) at 37 degrees C). HBO treatment was administered by placing pups in a chamber (3 ATA for 1 h) 1 h after hypoxia exposure. Brain injury was assessed based on ipsilateral hemispheric weight divided by contralateral hemispheric weight, light microscopy, and EM. Sensorimotor functional tests were administered at 5 weeks after hypoxia exposure. After HI, the ipsilateral hemisphere was 52.65 and 57.64% (P

Tumors frequently contain DNA copy number amplifications (amplicons) that are driven by overexpression of an oncogene but often lead to high expression of neighboring passenger genes. We hypothesized that proteins encoded on amplicons which are present at high frequency in particular types of cancer could serve as shared tumor rejection antigens. The ERBB2 (HER2) amplicon on 17q12-21 has a core region of approximately 280kB in size and is frequently present in multiple copies in 10-15% of breast and gastric cancers. Analysis of data from TCGA breast cancer project and multiple other mRNA expression studies show that ERBB2 overexpression is highly correlated with expression of some, but not all, adjacent genes. From the set of amplicon genes we selected MIEN, GRB7, PGAP3, PNMT, ORMDL3, and GSDMB as candidates for stimulating an immune response because these proteins are minimally expressed in normal tissues. Immunohistochemistry of tissue microarrays showed expression of these proteins in HER2+ breast cancer cells but not in HER2 non-amplified breast tumors. We used the epitope identification programs, NetCTLpan and NetMHCII (Center for Biological Sequence Analysis at the Technical University of Denmark) to identify several candidate peptides with high binding affinity Citation Format: Michael Berk, Arun Modi, Mona Patel, Li-Xin Wang, Gregory Plautz. Passenger genes on tumor-associated amplicons function as tumor rejection antigens. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A85.

We previously identified an induced serologic response in FVB-neuN mice bearing primary breast tumors following adoptive therapy with CD4+ T cells. Because the CD4+ T cells were initially primed with breast tumor progenitor cells, we tested whether the B cells induced in treated mice also recognized antigens expressed specifically by breast tumor progenitor cells. We generated hybridomas and then screened supernatant for binding to target cells by FACS analysis. We isolated three clones that produced IgG (mAb1-2, mAb2, and mAb3) which recognized cell surface molecules on tumorsphere cultures from a NeuN breast tumor line but not the parental adherent culture from which they were derived. We used a Her-2/neu antigen loss variant to show that Her-2/neu was not itself the antigen. Interestingly, the three mAbs also recognized 4T1tumorspheres, an independently derived breast tumor from another mouse strain, but not adherent 4T1 cultures. Moreover, the mAbs were not reactive with normal spleen, liver, or kidney cells. To investigate whether any of these mAbs had anti-tumor function we used Her-2/neuN transgenic mice which develop mammary adenocarcinoma starting at 5 months of age. We selected mice with a single spontaneous tumor in situ when tumors became palpable and visible. The mice received mAb1-2, mAb2, mAb3 (150 μg/dose) or PBS on day 0, day 1 then every other day until day 23. There was no toxicity from the treatment and mice treated with PBS or mAb3 all showed progressive tumor growth. However, administration of mAb1-2 inhibited primary tumor progression in 5/8 mice and mAb2 inhibited tumor progression in 9/13 mice (p Citation Format: Li-Xin Wang, Mona Patel, Michael Berk, Gregory Plautz. B cells induced during CD4+ T-cell mediated destruction of primary tumors in neuN mice produce mAbs that are capable of inhibiting spontaneous tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2551. doi:10.1158/1538-7445.AM2014-2551

A series of 3,3-disubstituted quinoxalinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The N-allyl (6b and 6f), N-cyclopropylmethyl (6a, 6g, 6h, and 6k) and N-carboalkoxy (6m-6y) substituted compounds displayed activity comparable or better than Efavirenz and GW420867X.

A series of 3,3-disubstituted quinoxalinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The N-allyl (6b and 6f), N-cyclopropylmethyl (6a, 6g, 6h, and 6k) and N-carboalkoxy (6m-6y) substituted compounds displayed activity comparable or better than Efavirenz and GW420867X.

Efavirenz (SUSTIVA TM ) is a potent non-nucleoside reverse transcriptase inhibitor. Due to the observation of breakthrough mutations of the reverse transcriptase enzyme during Efavirenz therapy, we sought to develop an optimized second generation series. To that end, SAR of the substituents on the aromatic ring was undertaken and the results are summarized here. The 5,6-difluoro ( 4f ) and the 6-methoxy ( 4m ) substituted benzoxazinones were determined to be equipotent, and as a result such substitution patterns will be incorporated in second generation scaffolds.

Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.

The oral gram-negative bacterium Actinobacillus actinomycetemcomitans is a major pathogen in human periodontal disease. Saline extraction releases a range of surface-associated components from this bacterium, including one which exhibits potent anti-proliferative activity as assessed by its capacity to inhibit DNA synthesis by human and other mammalian cells. Cultures incubated with this bacterial fraction for a prolonged period comprise a high proportion of cells containing a 4n level of DNA. Studies using hydroxyurea-synchronized cultures showed that cells treated with the surface-associated fraction were arrested in the G2 phase of the cell cycle and did not enter mitosis. This G2/M blockade was observed only when the bacterial fraction was added to the cells during early S phase. Our data also suggest that the active bacterial component binds to surface receptors expressed by the human cells and may act by a novel mechanism which involves down-regulation of cyclin B1 expression. The anti-proliferative activity of the bacterial fraction, purified by a combination of ammonium sulphate precipitation, HPLC anion exchange and gel filtration, has been shown to be an 8 kDa protein, which we have called gapstatin. Purified gapstatin was shown to be responsible for the the inhibitory effects of the surface-associated fraction on mammalian cells.

There is considerable interest in developing approaches to specifically target tumor progenitor cells. Our previous results demonstrated that adoptive transfer of CD4+ and CD8+ T cells primed with a breast cancer progenitor vaccine inhibited the progression of spontaneous primary tumors in neuN mice. Interestingly, post-treatment serum but not pre-treatment serum was reactive with surface molecules on the vaccine cells. This indicates that the transferred T cells resulted in uptake of tumor antigens and stimulation of host B cells. To characterize the antigenic targets, we generated hybridomas from spleen cells derived from treated mice. Three candidate clones which were strongly reactive with a neu-negative variant tumor line were subjected to two rounds of limiting dilution cloning. The mAb prepared from hybridoma #1 (IgG1) and hybridoma #2 (IgG2b) were each reactive against two independent tumor lines derived from spontaneous breast tumors in neuN mice (C2D1 and MMC5) when these cells were maintained in serum-free culture medium as tumorspheres. There was no reactivity against the same tumor cell lines when cultured as adherent monolayers in serum-containing medium nor was there reactivity against 3T3 adherent or tumorsphere cultures. Our previous analysis of tumorsphere cultures of C2D1 and MMC5 indicated that they express a panel of markers associated with tumor progenitor cells and have markedly enhanced per-cell tumorigenicity. Two of these antibodies have been purified by protein G or Protein A columns and retain binding to C2D1-tumorsphere cells, but not to C2D1 adherent cells. Importantly, these two antibodies can also bind to cultured 4T1-tumorsphere cells, an additional breast cancer cell line arising initially in BALB/c mice. These studies will allow us to identity corresponding antigens and determine expression on a broader array of spontaneous breast carcinomas in neuN mice. The epitopes recognized by these mAbs, which are expressed on progenitor cells from multiple tumor lines, might have importance as an immunotherapy target. Citation Format: Li-Xin Wang, Mona Patel, Michael Berk, Gregory E. Plautz. Monoclonal antibodies derived in neuN mice following successful T cell therapy of spontaneous breast tumors are specific for tumor progenitor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2853. doi:10.1158/1538-7445.AM2013-2853

A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

Until recently, minority and poor men have been characterized as "an invisible population," overlooked by public and private efforts to improve the health status of women, children, and the elderly.This study compares the health care experiences of racial and ethnic minority men with that of white men, and low socioeconomic status with those of higher status. MEASURES/SUBJECTS: Quality-of-care measures in multiple clinical domains are evaluated. The authors use data from several databases, including the National Health Interview Survey, Medical Expenditure Panel Survey, and Health Care Cost and Utilization Project State Inpatient Database. The relative difference between each racial/ethnic and socioeconomic group and a fixed reference group is used to assess differences in use of services. Statistical significance is assessed using z tests.Hispanic men were much less likely to receive colorectal cancer screening (relative risk [RR] range, 0.61-0.69), cardiovascular risk factor screening and management (RR, 0.84-0.88), and vaccinations (RR, 0.47-0.94). Black and Asian men were significantly less likely to have received selected preventive services (adult immunization and colorectal cancer screening). The differences in end-stage renal disease care that black and white men received were statistically significant (RR, 0.39-0.97), with black men consistently receiving worse care. For some measures of management of end-stage renal disease, Asian men received care that was similar to or better than that received by non-Hispanic whites.Minority men are at a markedly elevated risk for the receipt of poor health care quality. However, generalizations about "minority" men are likely to be misleading and incomplete. There is a considerable variation in the magnitude, direction, and significance of these risks.

A simple preparation of 2-carbomethoxy-2-azabicyclo[3.3.1]nonan-6-one ( 7 and its conversion to the racemic benzomorphans: 9 , 10 , 14 are described.

The total synthesis of prodigiosin ( 1 ), possessing the characteristic pyrrolylpyrromethene skeleton of a class of naturally-occurring polypyrroles, is detailed, The approach is based on the application of an inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate in a 1,2,4,5-teirazine → 1,2-diazine → pyrrole strategy for preparation of prodigiosin pyrrole ring B and the subsequent implementation of an intramolecular palladium(Il)-promoted 2,2′-diaryl (2,2′-bipyrrole) coupling for construction of the prodigiosin 2,2′-bipyrrole AB ring system.

Summary A study of the pi-facial selectivity of the Diels-Alder reaction of N -benzoyl 5-methoxycarbony 1–2-aza-oxabicyclo[2.2.2]oct-4-ene, a rigid electron deficient dienophile bearing two allylic axial heteroatom substituents, with 1-methoxy-3-trimethylsilyloxybutadiene, a representative electron rich diene, is detailed.

Etude de la cycloaddition des deux composes du titre avec le t-butyldimethylsiloxymethyl-2 cyclohexadiene-1,3